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Gut microbe ‘memory’ of obesity brings weight back

A recent paper in Nature found that the gut retains a “memory” of obesity through lasting changes in the makeup of the microbes living in the intestines. Even after weight loss, this altered microbiome makes it more likely that obesity will recur, according to the study headed by CIFAR Senior Fellow Eran Elinav (Weizmann Institute of Science).

Researchers put obese mice on a diet until they reached a lean weight, and all of their body systems — such as physical activity and food intake — returned to normal, with one notable exception.

“The only thing that remained altered was the gut microbiome. It ‘remembers’ that these mice were once obese,” says Elinav, who was in Portland, Ore. for CIFAR’s Humans & the Microbiome program meeting.

Although diet has been shown to change the gut microbiome within days, Elinav’s research demonstrates that the altered “obese” microbiome lasts for up to six months. What’s more, this microbe memory activated exaggerated weight gain when obese mice return to a high fat diet.

The study was led by Christoph Thaiss, a PhD student in Elinav’s lab in the immunology department, and pulled in researchers ranging from mathematicians to digestive specialists, including Elinav’s collaborating team headed by Prof. Eran Segal, also from the Weizmann Institute. Together, they developed unique methods to predict and control the weight gain function.

Machine learning has been a boon for microbiome research. Algorithms allow researchers to analyze hundreds of different species of bacteria that live inside the gut in ways that were previously impossible, says Elinav. In this study, algorithms successfully predicted the weight regain in 25 formerly obese mice and 25 control mice based only on the composition of their microbiome and history of obesity.

To determine the exact trigger for the weight gain, Elinav’s team narrowed their scope using genomic and metabolic tools. They identified 773 bacterial genes that were altered by a high fat diet. Of these, 189 were considered contributors, but no single gene was responsible. Instead, the microbiome as a whole appears to control the levels of two molecules that drive weight regain. These molecules, known as flavonoids, control the mice’s metabolism and energy expenditure. As the microbiome changes, these flavonoid levels drop and mice put on extra fat and cannot burn it off as quickly.

Algorithms successfully predicted the weight regain in 25 formerly obese mice and 25 control mice based only on the composition of their microbiome and history of obesity.

These animal models help frame years of human obesity research. More than 44 per cent of the world’s population is obese and 300 million adults are suffering from morbid obesity, according to the study. Many of these individuals will try to diet, but even when successful, 80 per cent will gain back the weight or surpass it within the following months.

Elinav’s lab has not developed a miracle pill for obesity, but they have found several ways to treat it in mice based on this new knowledge.
The first treatment tested was a fecal microbiome transplant. When researchers replaced the persistent gut microbiome from successfully dieting mice with that of naïve mice that were never obese, they regained weight at a normal rate.

The second and potentially more human-friendly option is supplementing drinking water with the missing flavonoids. Post-diet mice that were given a flavonoid drink every day did not put on weight as dramatically and their flavonoid levels returned to normal despite the altered microbiome. This treatment would introduce substances affected by the microbiome rather than the microbiome itself.

The microbiome memory and its affects may seem undesirable to some, but the study suggests it serves as an important “buffer.” Elinav believes microbes co-evolved with humans to preserve energy and avoid exaggerated weight fluctuations. “For millions of years, the fear was lack of nutrition, and our systems were designed to conserve energy until adequate feeding was available again. However, in the last 100 years we have been exposed to the exact opposite environmental conditions,” he says.

“The same energy buffering systems that helped us survive may now be turning against us.”